Habitual use of tobacco and alcohol leads to co-dependence and misuse of these drugs has imposed significant health risks on our society. Thus, efficacious treatments are urgently needed. As the majority of alcohol-dependent individuals are also nicotine-dependent, this co-dependence seems to make abstaining from alcohol more difficult. In ongoing studies to identify brain mechanisms of actions for nicotine (the principal addictive ingredient in tobacco) and alcohol, we use electrophysiological techniques to study acute neuronal function and possible neuronal interactions of these two drugs in mouse hippocampal brain tissue. The hippocampus is an important brain area that is known to regulate motivational behaviors, including reward and drug addiction, by both direct (via glutamatergic excitatory systems) and indirect (via GABAergic inhibitory systems) mechanisms. Alcohol is known to modify activities of excitatory glutamatergic (NMDA and AMPA) and inhibitory GABAergic (GABAA) receptors. Nicotine, in contrast, exerts its actions through nicotinic acetylcholine receptors (nAChRs) in the brain to increase neurotransmission. The 17 subtype of nAChRs is inhibited by alcohol, whereas the 1422 nAChR subtype is enhanced by alcohol. Our data show that in the hippocampus, nicotine increases both excitatory and inhibitory chemical communication between neurons (neurotransmission), but that acute alcohol application increases inhibitory and decreases excitatory neurotransmission. Thus, when these two drugs are used together, complex interactions arise to alter neurotransmission. Importantly, we found that inhibitory GABAergic neurotransmission is regulated by both 17 and 1422 subtypes, while the excitatory glutamatergic neurotransmission is controlled primarily by the 17 subtype in CA1 hippocampal neurons. The combined use of nicotine and alcohol produces specific increases in inhibitory synaptic neurotransmission in this brain area. Habitual alcohol drinking can cause brain neurotransmission deregulation, and we hypothesize that this deregulation may worsen when both drugs are used together. We propose to investigate nicotinic receptor regulation on the effects of alcohol on GABAergic and glutamatergic neurotransmission in mice that are chronically treated with alcohol or nicotine. Specific Aim 1 is designed to identify mechanisms of nicotine-induced glutamatergic and GABAergic activity in neurons from alcohol-treated mice. Specific Aim 2 is designed to investigate how chronic nicotine self-administration may modulate alcohol effects in glutamatergic and GABAergic function. Uncovering the mechanisms of chronic nicotine and alcohol effects on neurotransmission in brain may help to identify specific sites for drug development to treat alcohol and nicotine dependence.